Penicillins and cephalosporins are the most frequently and widely used β-lactam antibiotics in the clinic. However, the development of resistance to β-lactam antibiotics by different pathogens has had a damaging effect on maintaining the effective treatment of bacterial infections. (Coleman, K. Expert Opin. Invest. Drugs 1995, 4, 693; Sutherland, R. Infection 1995, 23 (4) 191; Bush, K, Cur. Pharm. Design 1999, 5, 839–845) The most significant known mechanism related to the development of bacterial resistance to the β-lactam antibiotics is the production of class-A, class-B and class-C serine β-lactamases. These enzymes degrade the β-lactam antibiotics, resulting in the loss of antibacterial activity. Class-A enzymes preferentially hydrolyze penicillins where as Class-C lactamases have a substrate profile favoring cephalosporin hydrolysis. (Bush, K.; Jacoby, G. A.; Medeiros, A. A. Antimicrob. Agents Chemother. 1995, 39, 1211). To date over 250 different β-lactamases have been reported (Payne, D. J,: Du, W and Bateson, J. H. Exp. Opin. Invest. Drugs 2000, 247.) and there is a need for a new generation of broad spectrum β-lactamase inhibitors. Bacterial resistance to these antibiotics could be greatly reduced by administering the β-lactam antibiotic in combination with a compound which inhibits these enzymes.
The commercially available β-lactamase inhibitors such as clavulanic acid, sulbactam and tazobactam are all effective against class-A producing pathogens. Clavulanic acid is clinically used in combination with amoxicillin and ticarcillin; similarly sulbactam with ampicillin and tazobactam with piperacillin. However, these compounds are ineffective against class C producing organisms. The mechanism of inactivation of class-A β-lactamases (such as PCI and TEM-1) has been elucidated. (Bush, K.; Antimicrob. Agents Chemother. 1993, 37, 851; Yang, Y.; Janota, K.; Tabei, K.; Huang, N.; Seigal, M. M.; Lin, Y. I.; Rasmussen, B. A. and Shlaes, D. M. J. Biol. Chem. 2000, 35, 26674–26682).
In 1981, the Beecham group disclosed 6-alkylidine penems of general structure 1 as inhibitors of β-lactamases. [N. F. Osborne, U.S. Pat. No. 4,485,110 (1984); N. F. Osborne, Eur. Pat. Appl. 81 301683.9, 1981; N. F. Osborne, Eur. Pat. Appl. 84301255.0; N. F. Osborne, Eur. Pat. Appl. 85100520.7; Eur. Pat. Appl. 85100521.5; Eur. Pat. Appl. 85300456-2; N. J. P. Broom; F. P. Harrington, PCT WO 94/10178; K. Coleman; J. E. Neale PCT WO 95/28935; K. Coleman; J. E. Neale PCT WO 95/17184]
                R=4-(Phenylsulfonyl)-thiophen-2-yl-sulfonyl 4-Carboxyphenylsulfamidophenyl-4yl-sulfonyl        

In addition to these methylidene based broad spectrum inhibitors, there were several transition state analogs based on boronic acids 3, 4 and acyl phosphanate 5 based inhibitors have been designed. [Martine, R.; Jones, J. B. Tetrahedron Lett. 1995, 36, 8399; Martine, R.; Gold, M.; Jones, J. B. Bioorg. Med. Chem. Lett. 1994, 4, 1229; Curley, K.; Pratt, R. F. J. Am. Chem. Soc. 1997, 119, 1529.; Rahil, J.; Pratt, R. F.; Biochem. J. 1991, 275, 793.; Rahil, J.; Pratt, R. F.; Biochemistry 1993, 32, 10763.]
The phosphonate based inhibitors were found to exclusively inhibit only the class C enzymes. In addition to these inhibitors several substituted succinic acid derivatives 6 were found to be potent inhibitors of metallo-β-lactamases. [Arakawa, Y.; Murakami, M.; Suzuki, K.; Ito, H.; Wacharotayankun, R.; Ohsuka, S.; Kato, N.; Ohta, M. Antimicrob. Agents Chemother., 1996, 40, 349.] A number of compounds such as acrylonitrile derivatives 7, oxopyrrolidine carboxylate derivatives 8, 2H,3H-benzimidazo[2,1-b]oxazole derivatives 9 and biphenyl tetrazole are reported to have weak β-lactamase inhibitor activity. [For recent review ref. (a) Payne, D. J.; Du, W.; Bateson, J. H.; Exp. Opin. Invest. Drugs 2000, 9, 247: (b) Sandanayaka, V. P.; Prashad, A. S. Current. Med. Chem. 2002, 9,1145: (c) Micetich, R. G.; salama, S. M.; Maiti, S. N.; Reddy, A.V.N.; Singh, R. Current. Med. Chem. 2002, 1, 193.] How ever, to-date there is no known β-lactamase inhibitor having the molecular structure of 4,7-dihydro-1,4-thiazepine-7-[bicyclic or tricyclic heteroaryl] substituted-3,6-dicarboxylic acid or their derivatives. However 1,4-thiazepine derivatives have been prepared in the past by three groups. [(a) Broom, N. J .P.; Farmer, T. H.; Osborne, N. F.; Tyler, J. W. J. Chem. Soc. Chem. Comm. 1992,1663; (b) Visentin, G.; Perrone, E.; Borghi, D.; Rizzo, V.; Alpegiani, M.; Bedeschi, A.; Corigli, R.; Rivola, G.; Franceschi, G. Heterocycles, 1992, 33, 859; (c) Didier, B.; Pierre, D.; Dominique, L.; Eliane, M.; Antonio, U. PCT, WO 2000/005246.]